Preparation of thiooxime cephalosporin

ABSTRACT

Compounds of the formula ##STR1## wherein A is ##STR2## R is hydrogen, lower alkyl, benzyl, p-methoxybenzyl, p-nitrobenzyl, diphenylmethyl, tri(lower alkyl)silyl, lower alkoxymethyl, 2,2,2-trichloroethyl, ##STR3## Y is halogen or lower alkoxy; R 1  is lower alkyl, phenyl, or substituted phenyl; and X is hydrogen, lower alkanoyloxy, ##STR4## or certain heterothio groups; R 4  is hydrogen or lower alkyl; R 5  is lower alkyl; are disclosed. These compounds, particularly the free acids, possess the useful pharmacological property of inhibiting β-lactamase enzymes as well as being useful as intermediates, particularly where R is a readily cleavable ester, in the preparation of antibacterially active 6α-methoxy penicillins and 7α-methoxy cephalosporins.

This application is a division of Ser. No. 748,425 filed on Dec. 8, 1976now U.S. Pat. No. 4,109,084.

BACKGROUND OF THE INVENTION

Welch, J. Org. Chem., Vol. 41, p. 2220-2222, discloses reacting6-aminopenicillanic acid (6-APA) with an arylsulfenyl chloride underaqueous conditions to yield a mixture of an aryl sulfenamide and adiarylsulfenimide 6-substituted penicillin.

Nudelman in U.S. Pat. No. 3,907,788 discloses reacting7-aminocephalosporanic acid (7-ACA) with an equimolar amount of asulfenyl derivative to yield a 7-sulfenamido cephalosporin.

The combination of an active antibacterial agent and an agent havingβ-lactamase inhibition are taught in U.S. Pat. Nos. 3,624,225,3,867,538, and 3,952,094.

Various acylated 7α-methoxy cephalosporins and 6α-methoxy penicillinsare disclosed as possessing useful antibacterial activity as note forexample U.S. Pat. Nos. 3,775,410, 3,780,031, 3,780,033, 3,780,037,3,843,641, 3,920,639, 3,960,845, 3,978,651, etc.

Also, 7-amino-7-substituted thio-cephalosporins and6-amino-6-substituted thio-penicillins are disclosed in U.S. Pat. Nos.3,840,533 and 3,855,233.

SUMMARY OF THE INVENTION

This invention relates to new thiooxime cephalosporin and penicillinderivatives of the formula ##STR5##

A represents ##STR6##

R represents hydrogen, lower alkyl, benzyl, p-methoxybenzyl,p-nitrobenzyl, diphenylmethyl 2,2,2-trichloroethyl, tri(loweralkyl)silyl, lower alkoxymethyl, ##STR7##

Y is halogen or lower alkoxy.

R₁ represents lower alkyl, phenyl, or substituted phenyl.

X represents hydrogen, lower alkanoyloxy, ##STR8## or certain heterothiogroups.

R₄ is hydrogen or lower alkyl.

R₅ is lower alkyl.

Also disclosed are methods of converting the compounds of formula I toantibacterially active 7-acyl-7α-methoxy cephalosporins and6-acyl-6α-methoxy penicillins.

DETAILED DESCRIPTION OF THE INVENTION

The various groups represented by the symbols have the meaning definedbelow and these definitions are retained throughout this specification.

The lower alkyl groups referred to throughout this specification includestraight or branched chain hydrocarbon groups containing 1 to 4 carbonatoms. Examples of the type of groups contemplated are methyl, ethyl,n-propyl, isopropyl, t-butyl, etc. The lower alkoxy groups include suchlower alkyl groups attached to an oxygen, e.g., methoxy, ethoxy,propoxy, etc.

The term halogen employed in the definition of the variable Y is meantto include the four common halogens, e.g. chlorine, bromine, fluorine oriodine, with chlorine being preferred.

The substituted phenyl groups include a single substituent selected fromhalogen (preferably chlorine or bromine), lower alkyl of 1 to 4 carbons(preferably methyl or ethyl), and lower alkoxy of 1 to 4 carbons(preferably methoxy or ethoxy).

Lower alkanoyloxy refers to a group of the formula ##STR9## lower alkylwherein lower alkyl is of 1 to 4 carbons, preferably wherein lower alkylis methyl.

The heterothio groups are ##STR10## wherein R₂ is hydrogen or loweralkyl of 1 to 4 carbons (preferably methyl or ethyl) and R₃ is hydrogen,lower alkyl of 1 to 4 carbons (preferably methyl or ethyl), methoxy,hydroxy, or halogen (preferably chlorine).

The compounds of formula I wherein A, Y, and R₁ are as defined above; Xis hydrogen, lower alkanoyloxy, ##STR11## or heterothio; and R ishydrogen, lower alkyl, benzyl, p-methoxybenzyl, p-nitrobenzyl,diphenylmethyl, tri(lower alkyl)silyl, lower alkoxymethyl or2,2,2-trichloroethyl; and prepared by reacting a 6-aminopenicillin or7-aminocephalosporin of the formula ##STR12## with a halosulfenylcompound of the formula

    (III) halo-S-R.sub.1

wherein halo is preferably chlorine or bromine. This reaction isperformed in an inert non-aqueous solvent such as methylene chloride,chloroform, ethyl acetate, dimethylformamide, tetrahydrofuran, etc.,with at least a molar excess, preferably 2 to 4 equivalents, of thesulfenyl compound of formula III. The reaction is performed at atemperature of from about -30° C. to about 30° C. for from about 1 toabout 24 hours. Preferably one or more acid scavengers such as propyleneoxide, butylene oxide, pyridine, tri(lower alkyl)amine, or crushedmolecular sieves are employed in the reaction and the reaction isperformed under an inert atmosphere, e.g. argon or nitrogen. When R ishydrogen, the compound of formula II is preferably converted to itstrimethylsilyl ester before reaction with the sulfenyl compound.

The compounds of formula I wherein X is pyridinium or carbamoylsubstituted pyridinium are prepared by reacting a compound of theformula (or its sodium salt) ##STR13## with pyridine or carbamoylsubstituted pyridine in a polar solvent such as water and in thepresence of a catalyst such as an alkali metal thiocyanate. U.S. Pat.No. 3,792,047 and German Offenlegungsschrift No. 2,234,280 both disclosemethods for reacting a cephalosporin so as to replace an acetoxy groupwith a pyridinium group.

Also, the compounds of formula I wherein X is heterothio can be preparedby reacting the compound of formula Ia with a mercaptan of the formula

    (IV) hetero-S-H

or an alkali metal (preferably sodium) mercaptan salt of the formula

    (V) hetero-S-alkali metal.

Methods for displacing the acetoxy group of a cephalosporin by aheterothio group are taught in various U.S. Pat. Nos. including3,855,213; 3,890,309; 3,892,737; etc.

The compounds of formula I wherein R is ##STR14## may be obtained bytreating the compound of formula II wherein R is hydrogen either beforeor after the reaction with the sulfenyl compound with one or two molesof a compound of the formula ##STR15## wherein halo is chlorine orbromine in an inert solvent such as dimethylformamide at or belowambient temperature.

Similarly, the compounds of formula I wherein R is ##STR16## areprepared by treating the compound of formula II wherein R is hydrogeneither before or after the reaction with the sulfenyl compound offormula III with a compound of the formula ##STR17## as taught by Ferreset al. in U.S. Pat. No. 3,860,579.

The thiooxime compounds of formula I particularly wherein R is a readilycleavable ester group such as t-butyl, benzyl, p-methoxybenzyl,p-nitrobenzyl, diphenylmethyl, and 2,2,2-trichloroethyl are valuable asintermediates in the preparation of various antibacterially active7-acyl-7α-methoxy cephalosporins and 6-acyl-6α-methoxy penicillins byseveral routes.

For example, the thiooxime compound of formula I can be reacted with atri(lower alkyl)phosphine, a tri(phenyl) or a tri(substitutedphenyl)phosphine, preferably triphenylphosphine, followed by treatmentwith an acid catalyst such as silica gel to yield the7β-amino-7α-substituted thio cephalosporin or 6β-amino-6α-substitutedthio penicillin of the formula ##STR18## wherein R₁ and A are as definedabove. The reaction between the thiooxime of formula I and the phosphineis performed in an inert solvent such as methylene chloride, chloroform,ethylacetate, dimethylformamide, tetrahydrofuran, etc., at about 0° C.to about 80° C. for from about 1 to about 24 hours. The reaction ispreferably performed under an inert atmosphere such as nitrogen orargon.

The resulting compound of formula VIII can then be acylated according toknown procedures to yield the compounds of the formula ##STR19## whichare then treated with a metal salt such as mercuric acetate, mercuricchloride, silver tetrafluoroborate, etc., in the presence of methanol astaught in German Offenlegungsschrift No. 2,360,945 of Dolfini et al. andby Applegate et al. in J. Org. Chem., Vol. 39, p. 2794-2796 to yield thecorresponding acylated 7α-methoxy cephalosporins or 6α-methoxypenicillins. The ester protecting group (i.e., R is t-butyl, benzyl,p-methoxybenzyl, p-nitrobenzyl, diphenylmethyl, 2,2,2-trichloroethyl)can then be removed according to known methods to yield the finalcompounds in the free acid form.

Alternatively, the compound of formula VIII can be treated with a metalsalt such as mercuric chloride in the presence of methanol as taught inBelgium Pat. No. 811,314 and by Jen et al. in J. Org. Chem., Vol. 38, p.2857-2859 to yield the corresponding 7β-amino-7α-methoxy cephalosporinor 6β-amino-6α-methoxy penicillin of the formula ##STR20## Acylationfollowed by the removal of the ester protecting group according to knownprocedures yields the desired final products.

Also, it has been discovered that the thiooximes of formula I can bereacted so as to yield the compound of formula X directly thus obviatingthe need to proceed via the intermediate of formula VIII. This reactioncan be performed by forming a solution of the thiooxime of formula I inan inert solvent such as methylene chloride, ethyl acetate, chloroform,dimethylformamide, tetrahydrofuran, etc., and adding under an inertatmosphere a tri(lower alkyl)phosphine, or a tri(phenyl)phosphine, or atri(substituted phenyl)phosphine, preferably triphenylphosphine. Thereaction mixture is kept at a temperature of from about 0° C. to about80° C. for from about 1 to about 24 hours with stirring. A metalcatalyst such as mercuric acetate, mercuric chloride, silvertetrafluoroborate, silver acetate, silver nitrate, silver perchlorate,lead acetate, or thallium acetate, preferably mercuric acetate, mercuricchloride, or silver tetrafluoroborate, and methanol are added to thereaction mixture. After about 1 to about 4 hours, the reaction mixtureis concentrated and the product of formula X is either isolated byconventional procedures or acylated directly to yield the desired6-acyl-6α-methoxy penicillin or 7-acyl-7α-methoxy cephalosporin.Alternatively, the thiooxime solution, phosphine, metal catalyst andmethanol can be combined into a reaction mixture at one time. Afterabout 4 to about 8 hours at from about 0° to about 80°, the reactionmixture is concentrated and the product of formula X is either isolatedor acylated directly.

The thiooxime compounds of formula I particularly those wherein R ishydrogen, lower alkoxymethyl, ##STR21## especially those wherein R ishydrogen, possess the useful pharmacological property of inhibitingβ-lactamase enzymes. Thus, these compounds can be combined with knownantibacterial agents which are susceptible to attack by β-lactamaseenzymes and enhance the antibacterial activity of these known agents.Examples of such known antibacterial agents include penicillins such aspenicillin G, penicillin V, ampicillin, amoxycillin, and epicillin,preferably ampicillin, and cephalosporins such as cephradine,cephalexin, cefazolin, cefoxitin, cefaloridine, cephaloglycin, andcefamandole, preferably cephradine. The thiooxime is present at fromabout 1% to about 90% by weight of the antibacterial combination. Sincea unit dose of most antibacterial agents for a 70 kg. mammal containsfrom about 250 mg. to about 2 g. of active ingredient, the thiooximewill be present at from about 2.5 mg. to about 1.8 g. in the unit dose.

The thiooxime and active antibacterial agent are formulated into acomposition along with a pharmaceutically acceptable carrier and otheringredients according to accepted pharmaceutical practice. Thecomposition is formulated so as to be administered orally orparenterally depending upon the mode of administration best suited forthe particular active antibacterial agent. Thus, a suitable injectablecomposition is a dry blend of the antibacterial agent, thiooxime, andsodium carbonate which is then reconstituted with water prior toadministration.

The following examples are illustrative of the invention. Alltemperatures are expressed in degrees centigrade.

EXAMPLE 17-[[(4-Methylphenyl)thio]imino]-3-[(acetyloxy)methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid

A mixture of 4 g. (16.7 mmol.) of7β-amino-3-[(acetyloxy)methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid (i.e., 7-ACA), 8.3 ml. (33.4 mmol.) ofbis(trimethylsilyl)-acetamide, pulverized molecular sieves (4A, ≈1000beads), 16 ml. of propylene oxide, and 320 ml. of methylene chloride isstirred at 26° for 1.5 hours under a nitrogen atmosphere. The reactionmixture is cooled to 0° and 10.07 g. (66.8 mmol.) of p-toluenesulfenylchloride is added dropwise over 20 minutes. The mixture is stirred atambient temperature for three hours, and then poured into 5% sodiumbicarbonate solution. The inorganic layer is acidified by the additionof 1 N HCl and extracted twice with 200 ml. of ethyl acetate. Thecombined organic extracts are dried over Na₂ SO₄, and then concentratedunder reduced pressure to a tan foam. The foam is triturated with ethylether to yield 1.75 g. of a tan crystalline material. Recrystallizationwithout heating from methanol/acetone/ether/hexane affords more paleyellow crystalline7-[[(4-methylphenyl)thio]imino]-3-[(acetyloxy)methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid; m.p. 204°-205.5°.

EXAMPLE 23-Methyl-7-[[(4-methylphenyl)thio]imino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid

A mixture of 5 g. (23.3 mmol.) of7β-amino-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid (i.e., 7-ADCA), 9.5 g. (46.6 mmol.) ofbis(trimethylsilyl)acetamide, pulverized molecular sieves (4A, ≈1000beads), 10 ml. of propylene oxide and 200 ml. of methylene chloride isstirred at 26° for 1.5 hours under a nitrogen atmosphere. The reactionmixture is cooled to 0° and 14.1 g. (88.5 mmol.) of p-toluenesulfenylchloride is added dropwise over 20 minutes. The mixture is stirred atambient temperature for three hours and then poured into 5% sodiumcarbonate solution. Bright yellow crystals form and are removed byfiltration. The filter cake is washed with 8% salt solution and driedunder a vacuum. Recrystallization from methanol/ethyl acetate yields apure sample of3-methyl-7-[[(4-methylphenyl)thio]imino]-8-oxo-5-thia-1-azabicyclo[4.2.0.]oct-2-ene-2-carboxylicacid; m.p. 186°-187°.

EXAMPLE 37-[[(4-Methylphenyl)thio]imino]-3-[[(1-methyl-1H-tetrazol-5-yl)-thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid

A mixture of 5 g. (15.9 mmol.) of7β-amino-3-[[(1-methyltetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]-oct-2-ene-2-carboxylicacid, 7.12 g. (34.9 mmol.) of bis(trimethylsilyl)acetamide, pulverizedmolecular sieves (4A, ≈1000 beads), 20 ml. of propylene oxide, and 400ml. of methylene chloride is stirred at 26° for 1.5 hours under anitrogen atmosphere. The reaction is cooled to 0° and 10.1 g. (63.6mmol.) of p-toluenesulfenyl chloride is added dropwise over 20 minutes.The mixture is stirred at ambient temperature for three hours and thenfiltered. The filtrate is extracted twice with 100 ml. of a 5% sodiumbicarbonate solution. The aqueous extracts are combined, acidified to pH2.3 by the addition of HCl, and extracted twice with 150 ml. of ethylacetate. The organic extracts are combined, dried (Na₂ SO₄), andconcentrated under reduced pressure to a brownish yellow solid.Trituration with ether followed by hexane affords a light tan solid; NMR(CDCl₃) δ 2.33 (S, 3H), 3.70 (S, 2H), 3.86 (S, 3H), 4.40 (S, 2H), 5.25(S, 1H), 7.26 (M, 4H); I.R. (KBr) 1770, 1715 cm⁻¹.

EXAMPLES 4-22

Following the procedures of examples 1 to 3 but employing the 7β-aminocephalosporanic acid shown in Col. I and the sulfenyl chloride shown inCol. II, one obtains the thiooxime shown in Col. III.

    ______________________________________                                        Col. I                Col. II                                                  ##STR22##            R.sub.1SCl                                              Col.III                                                                        ##STR23##                                                                    Ex.    X                R.sub.1                                               ______________________________________                                         4                                                                                    ##STR24##       CH.sub.3                                               5     H                                                                                               ##STR25##                                             6                                                                                    ##STR26##                                                                                      ##STR27##                                             7     H                C.sub.2 H.sub.5                                        8                                                                                    ##STR28##                                                                                      ##STR29##                                             9                                                                                    ##STR30##       CH.sub.3                                              10                                                                                    ##STR31##                                                                                      ##STR32##                                            11                                                                                    ##STR33##       CH.sub.3                                              12                                                                                    ##STR34##                                                             n-C.sub.3 H.sub.7                                                             13                                                                                    ##STR35##                                                                                      ##STR36##                                            14                                                                                    ##STR37##                                                             t-C.sub.4 H.sub.9                                                             15                                                                                    ##STR38##                                                                                      ##STR39##                                            16                                                                                    ##STR40##       CH.sub.3                                              17                                                                                    ##STR41##                                                                                      ##STR42##                                            18                                                                                    ##STR43##                                                                                      ##STR44##                                            19                                                                                    ##STR45##       C.sub.2 H.sub.5                                       20                                                                                    ##STR46##                                                                                      ##STR47##                                            21                                                                                    ##STR48##                                                                                      ##STR49##                                            22                                                                                    ##STR50##       CH.sub.3                                              ______________________________________                                    

example 233-methylene-7-[[(4-methylphenyl)thio]imino]-8-oxo-5-thia-1-azabicyclo[4.2.0]octane-2-carboxylicacid

Following the procedure of example 1 but substituting7β-amino-3-methylene-8-oxo-5-thia-1-azabicyclo[4.2.0]octane-2-carboxylicacid for the 7-ACA, one obtains3-methylene-7-[[(4-methylphenyl)thio]imino]-8-oxo-5-thia-1-azabicyclo[4.2.0]-octane-2-carboxylicacid.

Similarly, by employing the sulfenyl compounds shown in Col. II ofexamples 4 to 22 in the above procedure other compounds within the scopeof the invention are obtained.

EXAMPLE 243-Chloro-7-[[(4-methylphenyl)thio]imino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid

Following the procedure of example 1 but substituting7β-amino-3-chloro-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid for the 7-ACA, one obtains3-chloro-7-[[(4-methylphenyl)thio]imino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid.

EXAMPLES 25-35

Following the procedure of example 24 but employing the 3-halo or alkoxycephalosporin shown in Col. I and the sulfenyl chloride shown in Col.II, one obtains the thiooxime shown in Col. III.

    ______________________________________                                         Col. I               Col. II                                                  ##STR51##            R.sub.1SCl                                              Col. III                                                                       ##STR52##                                                                    Ex.        Y            R.sub.1                                               ______________________________________                                        25         Cl                                                                                          ##STR53##                                            26         Cl           CH.sub.3                                              27         Br                                                                                          ##STR54##                                            28         Br           C.sub.2 H.sub.5                                       29         I                                                                                           ##STR55##                                            30         F                                                                  n-C.sub. 3 H.sub.7                                                            31         OCH.sub.3                                                                                   ##STR56##                                            32         OC.sub.2 H.sub.5                                                                            ##STR57##                                            33         OCH.sub.3                                                                                   ##STR58##                                            34         OC.sub.2 H.sub.5                                                                            ##STR59##                                            35         OCH.sub.3    CH.sub.3                                              ______________________________________                                    

example 366-[[(4-methylphenyl)thio]imino]-3,3,-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylicacid

Following the procedure of example 1 but substituting6β-amino-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]-heptane-2-carboxylicacid (i.e., 6-APA) for the 7-ACA one obtains6-[[(4-methylphenyl)thio]imino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylicacid.

Also, by employing the sulfenyl chlorides of Col. II of examples 4 to 22within the above procedure other 6-substituted thiooxime penicillins areobtained.

EXAMPLE 373-[[4-(Aminocarbonyl)pyridino]methyl]-7-[[(4-methylphenyl)-thio]imino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid

An aqueous solution of the7-[[(4-methylphenyl)thio]-imino]-3-[(acetyloxy)methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]-oct-2-ene-2-carboxylicacid from example 1 and sodium bicarbonate is lyophilized to yield thesodium salt. An aqueous mixture of this sodium salt,4-pyridinecarboxamide, and potassium thiocyanate is heated at 50° for 24hours. The resulting solution is treated by chromatographic means toseparate out the3-[[(4-aminocarbonyl)pyridino]methyl]-7-[[(4-methylphenyl)thio]imino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid.

EXAMPLES 38-46

Following the procedure of Example 37 but employing the thiooxime shownin Col. I and the pyridine compound shown in Col. II, one obtains theproduct shown in Col. III.

    ______________________________________                                        Col. I                                                                         ##STR60##                                                                    Col. II                                                                        ##STR61##                                                                    Col. III                                                                       ##STR62##                                                                    Ex.   R.sub.1           Z                                                     ______________________________________                                        38    CH.sub.3                                                                                         ##STR63##                                            39                                                                                   ##STR64##        H                                                     40    C.sub.2 H.sub.5                                                                                  ##STR65##                                            41                                                                                   ##STR66##                                                                                       ##STR67##                                            42                                                                            t-C.sub.4 H.sub.9                                                                   H                                                                       43                                                                                   ##STR68##                                                                                       ##STR69##                                            44                                                                                   ##STR70##                                                                                       ##STR71##                                            45    CH.sub.3          H                                                     46                                                                                   ##STR72##                                                                                       ##STR73##                                            ______________________________________                                    

EXAMPLE 477-[[(4-Methylphenyl)thio]imino]-3-[[(1-oxopyridazin-3-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid

An aqueous solution of the7-[[(4-methylphenyl)thio]-imino]-3-[(acetyloxy)methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]-oct-2-ene-2-carboxylicacid from example 1 and sodium bicarbonate is lyophilized to yield thesodium salt. The sodium salt is dissolved in a mixture of acetone:water(1:1) and 1-oxopyridazine-3-thiol, sodium salt is added under a nitrogenatmosphere. The solution is heated at 60° for several hours, dilutedwith water, and acidified to yield7-[[(4-methylphenyl)thio]imino]-3-[[(1-oxopyridazin-3-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]-oct-2-ene-2-carboxylicacid.

EXAMPLES 48-62

Following the procedure of Example 47 but employing the thiooxime shownin Col. I and the heterothio compound shown in Col. II, one obtains theproducts shown in Col. III.

    ______________________________________                                        Col. I                    Col. II                                              ##STR74##                hetero-SH                                           Col. III                                                                       ##STR75##                                                                    Ex.   R.sub.1           hetero                                                ______________________________________                                        48                                                                                   ##STR76##                                                                                       ##STR77##                                            49    CH.sub.3                                                                                         ##STR78##                                            50    C.sub.2 H.sub.5                                                                                  ##STR79##                                            51                                                                                   ##STR80##                                                                                       ##STR81##                                            52                                                                                   ##STR82##                                                                                       ##STR83##                                            53                                                                                   ##STR84##                                                                                       ##STR85##                                            54    CH.sub.3                                                                                         ##STR86##                                            55                                                                                   ##STR87##                                                                                       ##STR88##                                            56    CH.sub.3                                                                                         ##STR89##                                            57    C.sub.2 H.sub.5                                                                                  ##STR90##                                            58                                                                                   ##STR91##                                                                                       ##STR92##                                            59    CH.sub.3                                                                                         ##STR93##                                            60                                                                                   ##STR94##                                                                                       ##STR95##                                            61    t-C.sub.4 H.sub.9                                                                                ##STR96##                                            62    i-C.sub.3 H.sub.7                                                                                ##STR97##                                        

EXAMPLE 637β-Amino-7α-[(4-methylphenyl)thio]-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid, diphenylmethyl ester (a)7-[[(4-Methylphenyl)thio]imino]-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid, diphenylmethyl ester

7.14 g. (45 mmol.) of p-toluenesulfenyl chloride in 50 ml. of drymethylene chloride is added dropwise with stirring under a nitrogenatmosphere to a cold solution (0°) of 7 g. (14.15 mmol.) of7β-amino-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]-oct-2-ene-2-carboxylicacid, diphenylmethyl ester in 600 ml. of dry methylene chloride and 60ml. of propylene oxide also containing 50 g. of crushed molecular sieves(4A). The reaction mixture is stirred, and the temperature allowed torise to 26° over a three hour period. The resulting mixture is filteredand the filtrate is concentrated to an oil under reduced pressure.Crystallization from methylene chloride/ethyl ether (0°) yields fineyellow needles; m.p. 154°-155°.

(b)7β-Amino-7α-[(4-methylphenyl)thio]-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo-[4.2.0]oct-2-ene-2-carboxylicacid, diphenylmethyl ester

1.32 g. of solid triphenylphosphine is added to a stirred solution of1.03 g. of7-[[(4-methylphenyl)thio]-imino]-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid, diphenylmethyl ester from part (a) in 100 ml. of methylenechloride at 26° under a nitrogen atmosphere. The mixture is stirred forfive hours at 26° at which time TLC indicated the absence of startingmaterial. The reaction mixture is then concentrated under reducedpressure and eluted directly onto a silica gel column. Elution with 5%ethyl acetate/methylene chloride yields7β-amino-7α-[(4-methylphenyl)thio]-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid, diphenylmethyl ester as a nearly colorless, clear oil; PMR (CDCl₃)δ 2.00 (Br.S, 2H, exchanged with D₂ O), 2.30 (S, 3H), 3.60 (S, 2H), 3.76(S, 3H), 4.26 (d of d, 2H, J=13), 4.73 (S, 1H), 6.86 (S, 1H), 7.30 (M,14H); I.R. (CHCl₃) 1775, 1715 cm⁻¹.

Alternatively, the titled product can be obtained by adding 2 g. of anacidic silica gel (Mallinckrodt Silicar CC-4) followed by 0.44 g. oftriphenylphosphine to a stirred solution of 1.03 g. of thiooxime productfrom part (a) in 50 ml. methylene chloride at 26° under a nitrogenatmosphere. The mixture is stirred at 26° for two hours, at which timeTLC indicated the absence of starting material. The reaction mixture isconcentrated under reduced pressure to approximately 20 ml. and eluteddirectly on a silica gel column (Mallinckrodt Silicar CC-7). Elutionwith 5% ethyl acetate/methylene chloride yields7β-amino-7α-[(4-methylphenyl)thio]-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo-[4.2.0]oct-2-ene-2-carboxylicacid, diphenylmethyl ester as an oil.

EXAMPLE 647β-Amino-7α-methylthio-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, diphenylmethyl ester (a)7-[(Methylthio)imino]-3-[[(1-methyl-1H-tetrazol-5-yl)thio]-methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid, diphenylmethyl ester

0.747 g. (9 mmol.) of methylsulfenyl chloride in 15 ml. of dry methylenechloride is added dropwise with stirring under a nitrogen atmosphere toa cold solution (0°) of 2 g. (3 mmol.) of7β-amino-3-[[(1-methyl-1H-tetrazol-5-yl)-thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid, diphenylmethyl ester in 160 ml. of dry methylene chloride and 16ml. of propylene oxide also containing 15 g. of crushed molecular sieves(4A). The reaction mixture is stirred and the temperature allowed torise to 26° over eight hours. The resulting mixture is filtered, and thefiltrate is concentrated under reduced pressure to a semi-crystallinesolid. Crystallization from methylene chloride/ethyl ether (0°) yieldswhite needles of7-[(methylthio)imino]-3-[[(1-methyl-1H-tetrazol-5-yl)thio]-methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid, diphenylmethyl ester; m.p. 213°-214°.

(b)7β-Amino-7α-methylthio-3-[[(1-methyl-1H-tetrazol-5-yl)-thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid, diphenylmethyl ester

Treating the thiooxime part from part (a) according to either of theprocedures set forth in Example 63(b) one obtains7β-amino-7α-methylthio-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid, diphenylmethyl ester as an oil; PMR (CDCl₃) δ 2.30 (Br.S, 2H),exchanged with D₂ O), 2.33 (S, 3H), 3.66 (S, 2H), 3.83 (S, 3H), 4.36 (M,2H), 4.78 (S, 1H), 6.90 (S, 1H), 7.33 (M, 10H); I.R. (CDCl₃) 1775, 1715cm⁻¹.

EXAMPLE 657-[[(4-Methylphenyl)thio]imino]-3-[(acetyloxy)methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid, diphenylmethyl ester

Following the procedure of example 63(a) but employing7β-amino-3-[(acetyloxy)methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid, diphenylmethyl ester as the starting material, one obtains7-[[(4-methylphenyl)thio]imino]-3-[(acetyloxy)methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid, diphenylmethyl ester following silica gel chromatography as ayellow oil: PMR (CDCl₃) δ 1.96 (S, 3H), 2.33 (S, 3H), 3.41 (M. 2H), 4.85(d of d, 2H, J=13), 5.26 (S, 1H), 6.91 (S, 1H), 7.28 (M, 14H); I.R.(CHCl₃) 1775, 1730, 1720 (sh) cm⁻¹.

EXAMPLES 66-87

Following the procedure of example 63(a) but employing the7β-amino-cephalosporanic acid ester shown below in Col. I and thesulfenyl chloride shown in Col. II, one obtains the thiooxime productshown in Col. III.

    __________________________________________________________________________    Col. I                                                                         ##STR98##                                                                    Col. II                                                                       R.sub.1SCl                                                                    Col. III                                                                       ##STR99##                                                                    Ex.                                                                              X           R              R.sub.1                                         __________________________________________________________________________    66 H                                                                                          ##STR100##    CH.sub.3                                        67                                                                                ##STR101##                                                                                ##STR102##    C.sub.2 H.sub.5                                 68                                                                                ##STR103##                                                                                ##STR104##                                                    n-C.sub.3 H.sub.7                                                             69                                                                                ##STR105## CH.sub.2CCl.sub.3                                                                             ##STR106##                                     70                                                                                ##STR107##                                                                                ##STR108##                                                                                   ##STR109##                                     71 H           Si(CH.sub.3).sub.3                                                                            ##STR110##                                     72                                                                                ##STR111## CH.sub.2CCl.sub.3                                                                             ##STR112##                                     73                                                                                ##STR113##                                                                                ##STR114##                                                                                   ##STR115##                                     74                                                                                ##STR116##                                                                                ##STR117##    CH.sub.3                                        75                                                                                ##STR118##                                                                t-C.sub.4 H.sub.9                                                                 ##STR119##                                                                76                                                                                ##STR120##                                                                t-C.sub.4 H.sub.9                                                                C.sub.2 H.sub.5                                                            77                                                                                ##STR121##                                                                                ##STR122##                                                    t-C.sub.4 H.sub.9                                                             78                                                                                ##STR123## CH.sub.2 CCl.sub.3                                                                            ##STR124##                                     79                                                                                ##STR125## CH.sub.2 OCH.sub.3                                                                           CH.sub.3                                        80                                                                                ##STR126##                                                                81 H           CH.sub.3       CH.sub.3                                        82                                                                                ##STR127##                                                                                ##STR128##                                                                                   ##STR129##                                     83                                                                                ##STR130##                                                                i-C.sub.3 H.sub.7                                                                 ##STR131##                                                                84                                                                                ##STR132##                                                                                ##STR133##                                                                                   ##STR134##                                     85                                                                                ##STR135##                                                                                ##STR136##    CH.sub.3                                        86                                                                                ##STR137##                                                                                ##STR138##    CH.sub.3                                        87                                                                                ##STR139##                                                                                ##STR140##    CH.sub.3                                        __________________________________________________________________________

the thiooxime products of examples 66 to 87 can then be reactedaccording to either of the procedures of example 63(b) to yield thecorresponding 7β-amino-7α-substituted thiocephalosporanic acid ester.

EXAMPLES 88-96

Following the procedure of example 63(a) but employing the 7β-aminocephalosporanic acid ester shown below in Col. I and the sulfenylchloride shown in Col. II, one obtains the thiooxime product shown inCol. III.

    ______________________________________                                        Col. I               Col. II                                                   ##STR141##          R.sub.1SCl                                               Col. III                                                                       ##STR142##                                                                   Ex.   R                   R.sub.1                                             ______________________________________                                        88                                                                                   ##STR143##         CH.sub.3                                            89                                                                                   ##STR144##                                                                                        ##STR145##                                         90                                                                                   ##STR146##                                                                                        ##STR147##                                         91                                                                                   ##STR148##                                                                                        ##STR149##                                         92    Si(CH.sub.3).sub.3                                                                                 ##STR150##                                         93    CH.sub.2CCl.sub.3   C.sub.2 H.sub.5                                     94                                                                                   ##STR151##         CH.sub.3                                            95                                                                                   ##STR152##                                                                                        ##STR153##                                         96                                                                                   ##STR154##         CH.sub.3                                            ______________________________________                                    

the thiooxime products of examples 88 to 96 can be reacted according toeither of the procedures of example 63(b) to yield the corresponding7β-amino-7α-substituted thio cephalosporanic acid ester.

EXAMPLES 97-110

Following the procedure of example 63(a) but employing the 7β-aminocephalosporanic acid ester shown below in Col. I and the sulfenylchloride shown in Col. II, one obtains the thiooxime product shown inCol. III.

    ______________________________________                                         ##STR155##                                                                   Ex.  R                 Y        R.sub.1                                       ______________________________________                                         97                                                                                 ##STR156##       Cl                                                                                      ##STR157##                                    98                                                                                 ##STR158##       Cl       CH.sub.3                                       99                                                                                 ##STR159##       Br       C.sub.2 H.sub.5                               100                                                                                 ##STR160##       F                                                                                       ##STR161##                                   101  CH.sub.2 CCl.sub.3                                                                              I                                                                                       ##STR162##                                   102                                                                                 ##STR163##       Cl       CH.sub.3                                      103                                                                                 ##STR164##       Cl                                                                                      ##STR165##                                   104                                                                                 ##STR166##       Cl       CH.sub.3                                      105                                                                                 ##STR167##       OCH.sub.3                                                                               ##STR168##                                   106  Si(CH.sub.3).sub.3                                                                              OC.sub.2 H.sub.5                                                                       CH.sub.3                                      107                                                                                 ##STR169##       OCH.sub.3                                                                               ##STR170##                                   108                                                                                 ##STR171##       OCH.sub.3                                                                               ##STR172##                                   109  CH.sub.2 CCl.sub.3                                                                              OC.sub.2 H.sub.5                                                                       C.sub.2 H.sub.5                               110  CH.sub.2 OCH.sub.3                                                                              OCH.sub.3                                                                               ##STR173##                                   ______________________________________                                    

the thiooxime products of examples 97 to 110 can be reacted according toeither of the procedures of example 63(b) to yield the corresponding7β-amino-7α-substituted thio cephalosporanic acid ester.

EXAMPLE 1116β-Amino-6α-[(4-methylphenyl)thio]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylicacid, 2,2,2-trichloroethyl ester (a)6-[[(4-Methylphenyl)thio]imino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylicacid, 2,2,2-trichloroethyl ester

0.262 ml. (1.88 mmol.) of triethylamine is added dropwise under anitrogen atmosphere to a cold (0°) mixture of 1 g. (1.88 mmol.) of6β-amino-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylicacid, 2,2,2-trichloroethyl ester p-toluenesulfonate salt in 80 ml. ofdry methylene chloride and 8 ml. of propylene oxide also containing 10g. of crushed molecular sieves (4A). After the addition is completed,0.9 g. (5.64 mmol.) of p-toluenesulfenyl chloride is added dropwise withstirring. The reaction mixture is stirred at 0° for two hours and at 26°for 30 minutes. The resulting mixture is filtered and the filtrate isevaporated to dryness under reduced pressure. Chromatography on a silicagel column (Mallinckrodt Silicar CC-7) (methylene chloride) yields6-[[(4-methylphenyl)-thio]imino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]-heptane-2-carboxylicacid, 2,2,2-trichloroethyl ester as a clear, bright yellow oil; PMR(CDCl₃) δ 1.60 (Br.S, 6H), 2.36 (S, 3H), 4.73 (S, 1H), 4.80 (S, 2H),5.73 (S, 1H), 7.33 (d of d, 4H); I.R. (CHCl₃) 1780, 1760 (Sh) cm⁻¹ ;U.V. (MeOH) 226 mμ (ε 8,300), 267 mμ (ε 3,600), 338 mμ (ε 3,600); massspectrum m/e 466 (M⁺).

(b)6β-Amino-6α-[(4-methylphenyl)thio]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylicacid, 2,2,2-trichloroethyl ester

The thiooxime product from part (a) is reacted with triphenylphosphineaccording to the second procedure set forth in Example 63(b) to yield6β-amino-6α-[(4-methylphenyl)-thio]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylicacid, 2,2,2-trichloroethyl ester as an oil: PMR (CDCl₃) δ 1.55 (S, 3H),1.63 (S, 3H), 2.36 (S, 5H, 3H after D₂ O exchange), 4.55 (S, 1H), 4.76(S, 2H), 5.50 (S, 1H), 7.30 (d of d, 4H, J=8); I.R. (CHCl₃) 1780, 1770(Sh) cm⁻¹ ; mass spectrum m/e 468 (M⁺).

EXAMPLE 1126α-Methoxy-6β-[(phenylacetyl)amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylicacid, 2,2,2-trichloroethyl ester

16.1 g. (34.54 mmol.) of the thiooxime product from example 111(a) and27.66 g. (103.6 mmol.) of triphenylphosphine are dissolved in 600 ml. ofmethylene chloride at 26°. A solution of 11.02 g. of mercuric acetate in150 ml. of methanol is immediately added and the reaction mixture isallowed to stir for 3.5 hours. The reaction mixture is evaporated todryness under reduced pressure and then redissolved in 600 ml. ofmethylene chloride and 150 ml. of propylene oxide. This solution ischilled to -10° and a solution of 25.8 g. of phenylacetylchloride in 80ml. of methylene chloride is added dropwise with stirring. After threehours, the reaction mixture is concentrated to an oil andchromatographed on silica gel (Mallinckrodt Silicar CC-7).6α-Methoxy-6β-[(phenacetyl)amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo-[3.2.0]heptane-2-carboxylicacid, 2,2,2-trichloroethyl ester is isolated as a clear oil: NMR (CDCl₃)δ 1.40 (S, 3H), 1.46 (S, 3H), 3.40 (S, 3H), 3.63 (S, 2H), 4.51 (S, 1H),4.81 (S, 2H), 5.66 (S, 1H), 7.30 (S, 5H).

EXAMPLE 1136-[(Methylthio)imino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylicacid, 2,2,2-trichloroethyl ester

Methylsulfenyl chloride is reacted with6β-amino-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylicacid, 2,2,2-trichloroethyl ester p-toluenesulfonate salt according tothe procedure of Example 111(a) and yields without chromatography acrystalline solid. Recrystallization of this crude product frommethylene chloride/hexane yields white crystalline6-[(methylthio)imino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylicacid, 2,2,2-trichloroethyl ester; m.p. 129°-130°.

EXAMPLES 114-132

Following the procedure of example 111 but employing the6β-amino-penicillanic ester shown in Col. I and the sulfenyl chlorideshown in Col. II, one obtains the thiooxime product shown in Col. III.

    ______________________________________                                         ##STR174##                                                                    ##STR175##                                                                   Ex.   R                  R.sub.1                                              ______________________________________                                        114   CH.sub.3                                                                                          ##STR176##                                          115   C.sub.2 H.sub.5                                                                                   ##STR177##                                          116                                                                           n-C.sub.3 H.sub.7                                                                   C.sub.2 H.sub.5                                                         117                                                                           t-C.sub.4 H.sub.9                                                                   CH.sub.3                                                                118                                                                           t-C.sub.4 H.sub.9                                                                    ##STR178##                                                             119   Si(CH.sub.3).sub.3                                                                                ##STR179##                                          120                                                                                  ##STR180##        CH.sub.3                                             121                                                                                  ##STR181##        C.sub.2 H.sub.5                                      122                                                                                  ##STR182##                                                                                       ##STR183##                                          123                                                                                  ##STR184##                                                                                       ##STR185##                                          124                                                                                  ##STR186##                                                                                       ##STR187##                                          125                                                                                  ##STR188##                                                             i-C.sub.3 H.sub.7                                                             126                                                                                  ##STR189##        C.sub.2 H.sub.5                                      127   CH.sub.2CCl.sub.3                                                                                 ##STR190##                                          128   CH.sub.2 OCH.sub.3                                                                                ##STR191##                                          129   CH.sub.2CCl.sub.3  C.sub.2 H.sub.5                                      130                                                                                  ##STR192##                                                                                       ##STR193##                                          131                                                                                  ##STR194##        CH.sub.3                                             132                                                                                  ##STR195##                                                                                       ##STR196##                                          ______________________________________                                    

the thiooxime products from examples 113 to 132 can be reacted as taughtin either example 111(b) or example 112 to yield the corresponding6β-amino-6α-substituted thio penicillanic acid ester or acylated6α-methoxy penicillanic acid ester.

EXAMPLE 1337β-Amino-7α-methoxy-3-[[(1-methyl-1H-tetrazol-5-yl)thio]-methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid, diphenylmethyl ester

0.264 g. (1 mmol.) of triphenylphosphine is added to a stirred solutionof 0.206 g. (0.33 mmol.)7-[[(4-methylphenyl)thio]imino]-3-[[(1-methyl-1H-tetrazol-5-yl)-thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid, diphenylmethyl ester from example 63(a) in 20 ml. of methylenechloride at 26° under a nitrogen atmosphere. The mixture is stirred at26° for 12 hours and then 0.106 g. (0.33 mmol.) of mercuric acetate in 5ml. of methanol is added. After two hours, the mixture is concentratedand ether is added precipitating out the desired7β-amino-7α-methoxy-3-[[(1-methyl-1H-tetrazol-5-yl)-thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid, diphenylmethyl ester.

Alternatively, the triphenylphosphine, the thiooxime compound fromexample 63(a), the methylene chloride, the mercuric acetate, and themethanol in the amounts set forth above are mixed together at one time.After five hours, the mixture is concentrated and ether is addedprecipitating out the desired7β-amino-7α-methoxy-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo-[4.2.0]oct-2-ene-2-carboxylicacid, diphenylmethyl ester.

EXAMPLE 1347β-[(Phenylacetyl)amino]-7α-methoxy-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid, diphenylmethyl ester

A reaction mixture of 0.264 g. (1 mmol.) of triphenylphosphine, 0.206 g.(0.33 mmol.) of7-[[(4-methylphenyl)-thio]imino]-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid, diphenylmethyl ester from example 63(a), 20 ml. of methylenechloride, 0.106 g. (0.33 mmol.) of mercuric acetate, and 5 ml. ofmethanol is prepared as set forth in the alternate procedure of example133. After five hours, the mixture is evaporated to dryness underreduced pressure. The residue is taken up in 25 ml. of methylenechloride and 5 ml. of propylene oxide. This solution is chilled to -10°and from 5 to 10 equivalents of phenylacetylchloride is added dropwisewith stirring. After 3.5 hours, the mixture is concentrated to an oil.Chromatography on silica gel (Mallinckrodt Silicar CC-7) affords7β-[(phenylacetyl]amino]-7α-methoxy-3-[[(1-methyl-1H-tetrazol-5-yl)thio]-methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid, diphenylmethyl ester as an oil: NMR (CDCl₃) δ 3.46 (S, 3H), 3.50(S, 2H), 3.66 (S, 2H), 3.83 (S, 3H), 4.36 (d, 2H, J=9 Hz), 5.00 (S, 1H),6.33 (Br.S, 1H), 6.90 (S, 1H), 7.33 (S, 15H).

EXAMPLE 135

The inhibition of a β-lactamase enzyme by the thiooxime compounds ofexamples 1 to 3 is demonstrated by the following procedure.

Two plates having a 350 ml. agar base are prepared. In one plate labeled"control", 150 ml. of agar seeded with 1 ml. of Micrococcus luteusSC2495 is added. To the second plate labeled "inhibitor plate", 150 ml.of agar containing 1 ml. of Micrococcus luteus SC2495, 0.3 μg./ml. ofcephradine and 0.13 units/ml. of cephradinase (a β-lactamase enzyme) isadded. It had previously been determined that this amount ofcephradinase would inactivate the cephradine and allow the Micrococcusluteus to grow. The compounds to be tested are then disced on bothplates and the zones of inhibition are compared.

    ______________________________________                                                        Zone of inhibition (mm.)                                                       Control        Inhibition                                    Compound         Plate          Plate                                         ______________________________________                                        Product of Ex. 1 0              40                                            Product of Ex. 2 0              30                                            Product of Ex. 3 0              37                                            ______________________________________                                    

Thus, the thiooximes of examples 1 to 3 while not active themselvesagainst Micrococcus luteus did inhibit the cephradinase.

What is claimed is:
 1. The process of preparing compounds of the formula##STR197## which comprises the step of treating a compound of theformula ##STR198## with at least a molar excess of a sulfenyl compoundof the formula

    R.sub.1 -S-halo

in an inert non-aqueous solvent at a temperature of from about -30° C.to about 30° for from about 1 to about 24 hours; wherein A is ##STR199##R is hydrogen, lower alkyl of 1 to 4 carbons, benzyl, p-methoxybenzyl,p-nitrobenzyl, diphenylmethyl, 2,2,2-trichloroethyl, tri(loweralkyl)silyl, or lower alkoxymethyl; R₁ is lower alkyl of 1 to 4 carbons;phenyl; or phenyl monosubstituted by lower alkyl of 1 to 4 carbons,lower alkoxy of 1 to 4 carbons or halogen Y is halogen or lower alkoxyof 1 to 4 carbons; X is hydrogen, ##STR200## lower alkyl wherein alkylis of 1 to 4 carbons, ##STR201## R₂ is hydrogen or lower alkyl of 1 to 4carbons; and halo is Br or Cl.
 2. The process of claim 1 wherein 2 to 4equivalents of the sulfenyl compound of the formula R₁ -S-Cl isemployed, the inert non-aqueous solvent is selected from the groupconsisting of methylene chloride, chloroform, ethyl acetate,dimethylformamide, and tetrahydrofuran, one or more acid scavengersselected from the group consisting of propylene oxide, butylene oxide,pyridine, tri(lower alkyl)amine, and crushed molecular sieves arepresent during the reaction, and the reaction is performed under aninert atmosphere.
 3. The process of claim 2 wherein A is ##STR202## 4.The process of claim 3 wherein X is ##STR203##
 5. The process of claim 4wherein R₁ is methyl and R is hydrogen or diphenylmethyl.
 6. The processof claim 4 wherein R₁ is 4-methylphenyl and R is hydrogen ordiphenylmethyl.
 7. The process of claim 3 wherein X is ##STR204##
 8. Theprocess of claim 7 wherein R₁ is methyl and R is hydrogen ordiphenylmethyl.
 9. The process of claim 7 wherein R₁ is 4-methylphenyland R is hydrogen or diphenylmethyl.
 10. The process of claim 3 whereinX is hydrogen.
 11. The process of claim 10 wherein R₁ is 4-methylphenyland R is hydrogen.
 12. The process of claim 2 wherein A is ##STR205##13. The process of claim 12 wherein R₁ is methyl and R is hydrogen or2,2,2-trichloroethyl.
 14. The process of claim 12 wherein R₁ is4-methylphenyl and R is hydrogen or 2,2,2-trichloroethyl.